Inosine triphosphate pyrophosphatase (ITPA protein) (EC 188.8.131.52) hydrolyzes deaminated purine nucleoside triphosphates, such as ITP and dITP, to their corresponding purine nucleoside monophosphate and pyrophosphate. In mammals, this enzyme is encoded by the Itpa gene. Using the Itpa gene-disrupted mouse as a model, we have elucidated the biological significance of the ITPA protein and its substrates, ITP and dITP. Itpa-/- mice exhibited peri- or post-natal lethality dependent on the genetic background. The heart of the Itpa-/- mouse was found to be structurally and functionally abnormal. Significantly higher levels of deoxyinosine and inosine were detected in nuclear DNA and RNA prepared from Itpa-/- embryos compared to wild type embryos. In addition, an accumulation of ITP was observed in the erythrocytes of Itpa-/- mice. We found that Itpa-/- primary mouse embryonic fibroblasts (MEFs), which have no detectable ability to generate IMP from ITP in whole cell extracts, exhibited a prolonged population-doubling time, increased chromosome abnormalities and accumulation of single-strand breaks in their nuclear DNA, in comparison to primary MEFs prepared from wild type embryos. These results revealed that (1) ITP and dITP are spontaneously produced in vivo and (2) accumulation of ITP and dITP is responsible for the harmful effects observed in the Itpa-/- mouse. In addition to its effect as the precursor nucleotide for RNA transcription, ITP has the potential to influence the activity of ATP/GTP-binding proteins. The biological significance of ITP and dITP in the nucleotide pool remains to be elucidated.
|ジャーナル||Mutation Research - Genetic Toxicology and Environmental Mutagenesis|
|出版ステータス||出版済み - 11 28 2010|
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